Question

DELIVERY

1. What were some of the difficulties with administering inhalational insulin?

2. Why can’t orally administered insulin be effectively used to treat diabetes (think about what type of molecule

insulin is)?

RELEASE

3. When glucose levels are low, insulin is NOT releases by the beta cells in the pancreas. Which channels are

open and close during this time?

4. When glucose enters the beta cells of the pancreas is that simple or facilitated diffusion? Explain how glucose

entering beta cells leads to insulin release into the bloodstream?

5. Is insulin made fresh every time you want to secrete it or is it stored and ready for release at all times?

ACTION

6. Why can’t insulin receptors be inside their target cell?

7. Once insulin is in the bloodstream, explain how it facilitates the entry of glucose into adipose tissues/cells. Why

does glucose enter and not exit the cell?

8. How does insulin increase the entry of glucose into hepatic (liver) cells during the fed state? What is meant by a

signal cascade?

9. In the fasted state, there is low insulin. Why does glucose leave liver cells instead of entering the cell?

Answer 1

Answer 1. After the discovery of Afrezza, it was a boon for patients with diabetes having trouble with subcutaneous injections everyday. But some of the difficulties faced with inhaled insulin were :

1 - It does not have required efficacy in people having a lung disease like COPD or asthma or those who smoke as it lead to decreased absorption of insulin in them

2 - It is not effective for people with Diabetes type 1 who require a long term and direct supply of insulin as Inhalational route takes more time than subcutaneous route.

3 - It can not be used in Diabetic Emergencies like Diabetic Ketoacidosis

4 Other side effects include - Low blood sugar, Cough, sore throat, fatigue, nausea etc

Answer 2. Orally administered insulin in its insulin form can not be used to treat diabetes because :

1 - Digestive juices in stomach and intestine will break down the insulin peptide bonds and it will never get the chance on get in your blood stream to break down sugar as it will get inactivated.

2 - Insulin is a hormone, with 51 amino acids which is quite large in molecular size as compared to other drugs which makes it harder to be converted into an oral stable pill.

3 - To fulfill the requirement of body for insulin, we would have to provide extremely higher doses to pass the first pass effect of liver and the effect of insulin will also get delayed in this process.

Answer 3. Insulin is regulated by voltage gated channels of Na⁺ , Ca²⁺ and K⁺ ions present in the Beta Islet cells of Pancreas. Presence of Glucose in blood stream produces ATP energy to run these channels and lack of glucose therefore blocks the opening and closing of these channels

Answer 4 . Glucose enters the beta cells through Glucose Transporter 2 and it is a facilitated diffusion .

Glucose leads to Insulin release through various steps:

1 - Increased levels of glucose in the circulation lead to increased glucose uptake into pancreatic beta cells through GLUT2, a glucose transporter.

2 - Increased intracellular glucose then leads to increased production of ATP, and an increase in the ATP/ADP ratio

3 - The increased ATP/ADP ratio leads to closing of the potassium channel and depolarization of the cell

4 - Cell depolarization opens a calcium channel

which leads to insulin secretion.

Answer 5 . Insulin is secreted fresh everytime body encounters glucose, and when body is in a state of increasing blood glucose. It is not stored and that is the reason why we prescribe patients to use insulin injection before their meals so that the glucose from that meal can be immediately metabolised.

Answer 6. Although all of our body cells respond to insulin. But the target cells of Insulin are the liver cells. Insulin encourages liver cells to conduct glucose uptake for storage and to use glucose as an energy source.

Insulin receptors can not be found in liver cells (target cells) because they are required in the stomach to sense the rise in glucose while liver is used to store glucose. If insulin receptors are found inside liver, then they will start interfering with the glucose storage.

Answer 7. The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of hexose transporters. In many tissues - muscle being a prime example - the major transporter used for uptake of glucose(called GLUT4) is made available in the plasma membrane through the action of insulin.

It does not exit the cell because it gets stored their and exits after its breakdown into pyruvate and after kreb cycle changes glucose into ATP and electorns.

Answer 8. Insulin is responsible for initiating the signal cascade in liver cells which then stimulate the breakdown or storage of glucose. In fed state, it facilitates transport of glucose to liver to convert into glycogen so that it can be used in future for energy production

Signal cascade is a series of chemical reactions which are initiated by a stimulus acting on a receptor that is transduced to the cell interior through second messengers and ultimately to effector molecules, resulting in a cell response to the initial stimulus. At each step of the signaling cascade, various controlling factors are involved to regulate cellular actions, responding effectively to cues about their changing internal and external environments.

Answer 9. Glucose does not leave liver cell directly. It leaves liver cells after getting converted into ATP to supply the energy requirement of the body. In fasted state, there is no availability of glucose in the stomach or outside liver, so it is not impossible to send glucose. Although fasting state stimulates liver to convert glycogen into glucose to recieve the needed energy.